Epitope vaccines provide a potential means for the treatment and prevention of infectious diseases, and for promoting the destruction of cancerous cells by an individual's immune system. It is well established that CD8+ cytotoxic T lymphocytes (CTL) play a crucial role in the eradication of infectious diseases and tumor cells by the mammalian immune system. MHC class I restricted epitope vaccines have been shown to confer protection in animal models, and it is widely believed that the development of epitope vaccines encoding human HLA-restricted CTL epitopes capable of conferring broad, effective, and non-ethnically biased population coverage is feasible.
Epitope-based vaccines offer a number of advantageous features, including the features that: they represent potent immunogens which can be constructed in a manner designed to target multiple conserved epitopes in a rapidly mutating pathogen (such as HCV or HIV), they can induce immune responses to subdominant epitopes (for example against a tumor associated antigen in a situation in which there is tolerance to a dominant epitope), they can be analogued to break tolerance or increase immunogenicity, and their use minimizes safety risks associated with the use of intact proteins or attenuated pathogens.
The immune system functions to discriminate molecules endogenous to an organism (“self” molecules) from material exogenous or foreign to the organism (“non-self” molecules). The human immune system recognizes antigens produced by its own cells, including pathogenic proteins (produced as a consequence of infection with an intracellular bacterial, viral or parasitic pathogen), and aberrant self-proteins (mutated self proteins expressed as a consequence of a cancerous process) by means of the major histocompatibility complex (MHC). More specifically, MHC molecule/MHC peptide complexes interact with antigen-specific T-cell receptors (TCR) to provide a context for the recognition of antigens by effector T-cells. Activation of effector T-cells triggers an immune response.
MHC/peptide complexes are displayed on the surface of antigen-presenting cells (APC), and most often consist of short protein segments (i.e., T-cell Epitopes) held in a pocket-like groove of an MHC class I or class II molecules. Typically, MHC class I ligands comprise 8-11 amino acids and are derived from endogenously expressed proteins which are degraded by cytosolic proteases. MHC class I molecules show preferential restriction to CD8+ cells. (A. Abbas et. al., Cellular and Molecular Immunology, 4th ed. 2000, Chapter 4, pp 63-73). In order for a T-cell epitope to be highly immunogenic it must not only promote stable enough TCR binding for activation to occur, but the TCR must also have a high enough off-rate that multiple TCR molecules can interact sequentially with the same peptide-MHC complex (A. Kalergis et al., Nature Immunol 2001, 2:229-234).
The tripartite interaction of the: 1) T-cell Receptor (TCR) with, 2) a major histocompatibility complex (MHC) molecule, or human leukocyte antigen (HLA) molecule, bound to, 3) an antigenic peptide derived from a pathogenic agent or cancerous cell, is crucial for eliciting a specific immune response against a cell expressing the immunologically relevant antigen. Recognition of a MHC class I-peptide complex by a TCR found on the surface of CD8+ cytotoxic T lymphocyte (CTL) activates an immune response which ultimately results in destruction (e.g., apoptosis) of the peptide-presenting cell.
The pathway from protein sequence analysis to vaccine development requires the development of binding assays for testing the affinity of candidate epitopes to particular MHC molecules, the establishment of in vitro assays suitable for evaluating the T-cell response, and ultimately in vivo testing of the immunogenicity and efficacy of a particular immunogenic composition. T-cell epitopes can be empirically determined by numerous experimental approaches, including peptide mapping, screening of combinatorial peptide libraries, production and screening of expression libraries derived from tissues of interest, or elution and sequencing of naturally occurring peptides from MHC molecules. Depending upon the nature of the target protein, empirical determination can be too expensive in terms of time, labor, and resources to be practical. Thus, there is considerable incentive to utilize data-driven computational methods, as a high throughput alternative to empirical work.
Although there are a wide variety of sequence-based methods for T-cell epitope identification, there is an unmet need for data processing systems which provide analytical methods for the identification and/or modification of known, or predicted, T-cell epitopes. In particular there is a need to identify modifications that confer T-cell epitopes with the ability to elicit stronger cellular immune responses because of more efficient antigen processing and/or presentation.